JP2014516953A5

JP2014516953A5 -

Info

Publication number: JP2014516953A5
Application number: JP2014510478A
Authority: JP
Filing date: 2012-05-10
Publication date: 2015-06-25
Anticipated expiration: 2032-05-10

Claims

At least one monoclonal antibody, in an amount of 40 mg / mL to 300 mg / mL, that specifically binds to PCSK9 comprising the amino acid of SEQ ID NO: 1, and 0.05 mM to 40 mM An amount of a pharmaceutically acceptable buffer, and an amount of 0.01 % w / v to 20 % w / v of a pharmaceutically acceptable surfactant, and 0.5 % w / v to 10 % w A stable formulation comprising at least one pharmaceutically acceptable stabilizer of / v and having a pH of 4.0 to 6.0 .

Monoclonal antibodies
a) a light chain variable region comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 23, and a heavy chain variable region comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 49, or b) a SEQ ID NO: A light chain variable region comprising an amino acid sequence that is at least 90% identical to 12, and a heavy chain variable region comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 67, or
c) a light chain variable region comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 465, and a heavy chain variable region comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 463, or
d ) a light chain variable region comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 461 and a heavy chain variable region comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 459, or
e ) a light chain variable region comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 485 and a heavy chain variable region comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 483; or
f ) a light chain variable region comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 582 and a heavy chain variable region comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 583 , or
g) Light chain complementarity determining region (CDR) 1 (CDRL1) of the CDRL1 sequence in SEQ ID NO: 23, CDRL2 of the CDRL2 sequence in SEQ ID NO: 23 and CDRL3 of the CDRL3 sequence in SEQ ID NO: 23, and the weight of the CDRH1 sequence in SEQ ID NO: 49 Strand complementarity determining region (CDR) 1 (CDRH1), CDRH2 of CDRH2 sequence in SEQ ID NO: 49 and CDRH3 of CDRH3 sequence in SEQ ID NO: 49, or
h) Light chain complementarity determining region (CDR) 1 (CDRL1) of the CDRL1 sequence in SEQ ID NO: 465, CDRL2 of the CDRL2 sequence in SEQ ID NO: 465 and CDRL3 of the CDRL3 sequence in SEQ ID NO: 465, and the weight of the CDRH1 sequence in SEQ ID NO: 463 Strand complementarity determining region (CDR) 1 (CDRH1), CDRH2 of CDRH2 sequence in SEQ ID NO: 463, CDRH3 of CDRH3 sequence in SEQ ID NO: 463, or
i) Light chain complementarity determining region (CDR) 1 (CDRL1) of the CDRL1 sequence in SEQ ID NO: 12, CDRL2 of the CDRL2 sequence in SEQ ID NO: 12 and CDRL3 of the CDRL3 sequence in SEQ ID NO: 12, and the weight of the CDRH1 sequence in SEQ ID NO: 67 Strand complementarity determining region (CDR) 1 (CDRH1), CDRH2 of CDRH2 sequence in SEQ ID NO: 67 and CDRH3 of CDRH3 sequence in SEQ ID NO: 67, or
j) Light chain complementarity determining region (CDR) 1 (CDRL1) of the CDRL1 sequence in SEQ ID NO: 461, CDRL2 of the CDRL2 sequence in SEQ ID NO: 461, CDRL3 of the CDRL3 sequence in SEQ ID NO: 461, and the weight of the CDRH1 sequence in SEQ ID NO: 459 Strand complementarity determining region (CDR) 1 (CDRH1), CDRH2 of CDRH2 sequence in SEQ ID NO: 459 and CDRH3 of CDRH3 sequence in SEQ ID NO: 459, or
k) Light chain complementarity determining region (CDR) 1 (CDRL1) of the CDRL1 sequence in SEQ ID NO: 485, CDRL2 of the CDRL2 sequence in SEQ ID NO: 485 and CDRL3 of the CDRL3 sequence in SEQ ID NO: 485, and the weight of the CDRH1 sequence in SEQ ID NO: 483 Strand complementarity determining region (CDR) 1 (CDRH1), CDRH2 of CDRH2 sequence in SEQ ID NO: 483 and CDRH3 of CDRH3 sequence in SEQ ID NO: 483, or
1) Light chain complementarity determining region (CDR) 1 (CDRL1) of the CDRL1 sequence in SEQ ID NO: 582, CDRL2 in the CDRL2 sequence in SEQ ID NO: 582 and CDRL3 in the CDRL3 sequence in SEQ ID NO: 582, and the weight of the CDRH1 sequence in SEQ ID NO: 583 Strand complementarity determining region (CDR) 1 (CDRH1), CDRH2 of CDRH2 sequence in SEQ ID NO: 583 and CDRH3 of CDRH3 sequence in SEQ ID NO: 583
A stable formulation according to claim 1 comprising

The monoclonal antibody comprises a light chain complementarity determining region (CDR) 1 (CDRL1) of the CDRL1 sequence in SEQ ID NO: 23, a CDRL2 sequence of CDRL2 in SEQ ID NO: 23 and a CDRL3 sequence of CDRL3 in SEQ ID NO: 23, and a CDRH1 sequence in SEQ ID NO: 49 The stable formulation according to claim 2, comprising a heavy chain complementarity determining region (CDR) 1 (CDRH1) of CDRH2 of CDRH2 in SEQ ID NO: 49 and CDRH3 of CDRH3 in SEQ ID NO: 49.

4. The stable formulation of claim 3, wherein the heavy chain comprises CDR1 comprising SEQ ID NO: 308, CDR2 comprising SEQ ID NO: 175, and CDR3 comprising SEQ ID NO: 180.

4. The stable formulation of claim 3, wherein the heavy chain comprises CDR1 comprising SEQ ID NO: 368, CDR2 comprising SEQ ID NO: 175, and CDR3 comprising SEQ ID NO: 180.

4. The stable formulation of claim 3, wherein the light chain comprises CDR1 comprising SEQ ID NO: 158, CDR2 comprising SEQ ID NO: 162, and CDR3 comprising SEQ ID NO: 395.

7. The stable formulation of claim 6, wherein the heavy chain comprises CDR1 comprising SEQ ID NO: 308, CDR2 comprising SEQ ID NO: 175, and CDR3 comprising SEQ ID NO: 180.

7. The stable formulation of claim 6, wherein the heavy chain comprises CDR1 comprising SEQ ID NO: 368, CDR2 comprising SEQ ID NO: 175, and CDR3 comprising SEQ ID NO: 180.

The stable formulation of claim 2, wherein each CDR is defined according to a Kabat definition or Chothia definition or combination of Kabat and Chothia definitions or an AbM definition or contact definition of a CDR.

10. The stable formulation of claim 9, wherein each CDR is defined according to the Kabat CDR definition.

10. The stable formulation of claim 9, wherein each CDR is defined according to Chothia's CDR definition.

Monoclonal antibodies
a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 23, and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 49;
b) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 465, and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 463;
c) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 12, and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 67;
d) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 461, and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 459,
e) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 485, and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 483, or f) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 582, and of SEQ ID NO: 583 The stable formulation of claim 2, comprising a heavy chain variable region comprising an amino acid sequence.

Monoclonal antibodies
a. The light chain constant sequence of SEQ ID NO: 156;
b. The light chain constant sequence of SEQ ID NO: 157,
c. The heavy chain constant sequence of SEQ ID NO: 154,
d. The heavy chain constant sequence of SEQ ID NO: 155,
e. The light chain constant sequence of SEQ ID NO: 156 and the heavy chain constant sequence of SEQ ID NO: 154,
f. The light chain constant sequence of SEQ ID NO: 157 and the heavy chain constant sequence of SEQ ID NO: 154,
g. The light chain constant sequence of SEQ ID NO: 156 and the heavy chain constant sequence of SEQ ID NO: 155, or
h. The light chain constant sequence of SEQ ID NO: 157 and the heavy chain constant sequence of SEQ ID NO: 155
The stable formulation according to claim 2, further comprising:

The stable formulation of claim 2, wherein the pharmaceutically acceptable buffer is selected from the group consisting of glutamate, phosphate, phosphate buffered saline, sodium acetate, sodium citrate, and Tris buffer.

The stable formulation according to claim 14 , wherein the pharmaceutically acceptable buffer is sodium acetate.

16. A stable formulation according to claim 15 wherein the pharmaceutically acceptable buffer is present in an amount of 10-20 mM.

The stable formulation according to claim 2, wherein the pharmaceutically acceptable surfactant is polysorbate 80 or polysorbate 20.

The stable formulation of claim 16 , wherein the pharmaceutically acceptable surfactant is polysorbate 80.

The stable formulation according to claim 16 , wherein the pharmaceutically acceptable surfactant is polysorbate 20.

20. A stable formulation according to any of claims 17, 18 or 19, wherein the pharmaceutically acceptable surfactant is present in an amount of 0.004 % w / v to 0.01 % w / v.

A stable pharmaceutically acceptable stabilizer according to any one of the preceding claims, wherein the pharmaceutically acceptable stabilizer is selected from the group consisting of polyhydroxy hydrocarbons, disaccharides, polyols, proline, arginine, lysine, methionine, taurine, and benzyl alcohol. Formulation.

The stable formulation of claim 21 , wherein the stabilizer is a polyhydroxy hydrocarbon selected from the group consisting of sorbitol, mannitol, and glycerol.

21. The stable formulation of claim 20 , wherein the stabilizer is sorbitol.

The stable formulation according to claim 21 , wherein the stabilizer is a disaccharide selected from the group consisting of sucrose, maltose, lactose, fructose, and trehalose.

21. The stable formulation of claim 20 , wherein the stabilizer is sucrose.

26. The stable formulation of claim 25 , wherein the stabilizer is present in an amount of 9 % w / v.

21. The stable formulation of claim 20 , wherein the stabilizer is proline.

28. The stable formulation of claim 27 , wherein proline is present in an amount of 2 % to 3% w / v.

27. The stable formulation according to claim 26 , having a pH of 5.0 to 5.5 .

29. The stable formulation according to claim 28 , having a pH of 5.0 to 5.5 .

27. The stable formulation of claim 26 , having a viscosity of 30 cP or less at 25 ° C.

29. The stable formulation of claim 28 , having a viscosity of 30 cP or less at 25 ° C.

29. The stable formulation of claim 28 , wherein the amount of monoclonal antibody is 70 mg / mL to 150 mg / mL, and the stable formulation has a viscosity of 12 cP or less at 25 [deg.] C.

30. The stable formulation of claim 29 having an osmotic pressure of 250 mOsmol / kg to 350 mOsmol / kg.

31. The stable formulation according to claim 30 , having an osmotic pressure of 250 mOsmol / kg to 350 mOsmol / kg.

30. The stable formulation of claim 29 , which remains stable for at least 3, 6, 12, or 24 months.

32. The stable formulation of claim 30 , which remains stable for at least 3, 6, 12, or 24 months.

Claim 36 comprising a heavy chain variable region is at least 90% identical to the amino acid sequence of the light chain variable region and SEQ ID NO: 49, at least 90% identical to monoclonal antibodies to the amino acid sequence of SEQ ID NO: 23 Stable formulation.

The monoclonal antibody comprises a light chain complementarity determining region (CDR) 1 (CDRL1) of the CDRL1 sequence in SEQ ID NO: 23, a CDRL2 sequence of CDRL2 in SEQ ID NO: 23 and a CDRL3 sequence of CDRL3 in SEQ ID NO: 23, and a 37. The chain complementarity determining region (CDR) 1 (CDRH1), CDRH2 of CDRH2 sequence in SEQ ID NO: 49 and CDRH3 of CDRH3 sequence in SEQ ID NO: 49, wherein the monoclonal antibody is 120 mg / mL to 140 mg / mL A stable formulation.

The stable antibody according to claim 36, wherein the monoclonal antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 23 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 49, and the monoclonal antibody is 120 mg / mL to 140 mg / mL. Preparation.

A heavy chain comprising CDR1 comprising SEQ ID NO: 308, a CDR2 comprising SEQ ID NO: 175, a CDR3 comprising SEQ ID NO: 180, a light chain comprising CDR1 comprising SEQ ID NO: 158, a CDR2 comprising SEQ ID NO: 162, and a SEQ ID NO: 395 37. The stable formulation of claim 36, wherein the monoclonal antibody comprises from 120 mg / mL to 140 mg / mL.

The heavy chain comprises CDR1 comprising SEQ ID NO: 368, CDR2 comprising SEQ ID NO: 175, CDR3 comprising SEQ ID NO: 180, CDR1 comprising light chain comprising SEQ ID NO: 158, CDR2 comprising SEQ ID NO: 162, SEQ ID NO: 395 37. The stable formulation of claim 36, wherein the monoclonal antibody comprises from 120 mg / mL to 140 mg / mL.

Claim 37 monoclonal antibody comprising a heavy chain variable region is at least 90% identical to the amino acid sequence of the light chain variable region and SEQ ID NO: 49, at least 90% identical to the amino acid sequence of SEQ ID NO: 23 Stable formulation.

The monoclonal antibody is a light chain complementarity determining region (CDR) 1 (CDRL1) of the CDRL1 sequence in SEQ ID NO: 23, a CDRL2 sequence of CDRL2 in SEQ ID NO: 23 and a CDRL3 sequence of CDRL3 in SEQ ID NO: 23, and a heavy chain complementation determination in SEQ ID NO: 49 38. The stable formulation of claim 37, comprising region (CDR) 1 (CDRH1), CDRH2 of CDRH2 sequence in SEQ ID NO: 49 and CDRH3 of CDRH3 sequence in SEQ ID NO: 49, wherein the monoclonal antibody is 120 mg / mL to 140 mg / mL .

The stable antibody according to claim 37, wherein the monoclonal antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 23 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 49, and the monoclonal antibody is 120 mg / mL to 140 mg / mL. Preparation.

A heavy chain comprising CDR1 comprising SEQ ID NO: 308, a CDR2 comprising SEQ ID NO: 175, a CDR3 comprising SEQ ID NO: 180, a light chain comprising CDR1 comprising SEQ ID NO: 158, a CDR2 comprising SEQ ID NO: 162, and a SEQ ID NO: 395 38. The stable formulation of claim 37, wherein the monoclonal antibody is from 120 mg / mL to 140 mg / mL.

The heavy chain comprises CDR1 comprising SEQ ID NO: 368, CDR2 comprising SEQ ID NO: 175, CDR3 comprising SEQ ID NO: 180, CDR1 comprising light chain comprising SEQ ID NO: 158, CDR2 comprising SEQ ID NO: 162, SEQ ID NO: 395 38. The stable formulation of claim 37, wherein the monoclonal antibody is from 120 mg / mL to 140 mg / mL.

37. The stable formulation of claim 36 , wherein the monoclonal antibody comprises a light chain variable region that is at least 90% identical to SEQ ID NO: 465 and a heavy chain variable region that is at least 90% identical to SEQ ID NO: 463.

38. The stable formulation of claim 37 , wherein the monoclonal antibody comprises a light chain variable region that is at least 90% identical to SEQ ID NO: 465 and a heavy chain variable region that is at least 90% identical to SEQ ID NO: 463.

Light chain variable region monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 465, and comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 463, as well as according to claim 36 the amount of monoclonal antibody is 0.99 mg / mL A stable formulation.

A stable formulation,
a. A monoclonal antibody in an amount of 70 mg / mL to 200 mg / mL,
i) a light chain variable region comprising an amino acid sequence having at least 90% identity to the sequence of SEQ ID NO: 23, and a heavy chain comprising an amino acid sequence having at least 90% identity to the sequence of SEQ ID NO: 49 Variable region, or
ii) the light chain complementarity determining region (CDR) 1 (CDRL1) of the CDRL1 sequence in SEQ ID NO: 23, the CDRL2 sequence of CDRL2 in SEQ ID NO: 23 and the CDRL3 of the CDRL3 sequence in SEQ ID NO: 23, and the heavy chain complementarity determining region in SEQ ID NO: 49 (CDR) 1 (CDRH1), CDRH2 of CDRH2 sequence in SEQ ID NO: 49 and CDRH3 of CDRH3 sequence in SEQ ID NO: 49, or
iii) a monoclonal antibody comprising a light chain variable region comprising the amino acid sequence of SEQ ID NO: 23 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 49 ;
(B) 10 mM sodium acetate,
(C) 9.0 % w / v sucrose,
(D) 0.004 % to 0.01 % w / v polysorbate 20 or polysorbate 80, and (e) a pH of 5.2 .
A stable formulation comprising

A stable formulation,
(A) a monoclonal antibody in an amount of 70 mg / mL to 200 mg / mL ,
i) a light chain variable region comprising an amino acid sequence having at least 90% identity to the sequence of SEQ ID NO: 23, and a heavy chain comprising an amino acid sequence having at least 90% identity to the sequence of SEQ ID NO: 49 Variable region, or
ii) the light chain complementarity determining region (CDR) 1 (CDRL1) of the CDRL1 sequence in SEQ ID NO: 23, the CDRL2 sequence of CDRL2 in SEQ ID NO: 23 and the CDRL3 of the CDRL3 sequence in SEQ ID NO: 23, and the heavy chain complementarity determining region in SEQ ID NO: 49 (CDR) 1 (CDRH1), CDRH2 of CDRH2 sequence in SEQ ID NO: 49 and CDRH3 of CDRH3 sequence in SEQ ID NO: 49, or
iii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 23 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 49
Including monoclonal antibodies,
(B) 10 mM sodium acetate,
(C) 2.0 % to 3.0% w / v proline,
(D) 0.01 % w / v polysorbate 20 or polysorbate 80, and (e) a pH of 5.0 .
A stable formulation comprising

A pharmaceutical composition for lowering serum LDL cholesterol in a patient, at least one anti-PCSK9 antibody comprises a dose of 14Mg～480mg, the Re their lowers serum LDL cholesterol levels by at least 30%, pharmaceutical compositions Thing .

A pharmaceutical composition for treating or preventing a cholesterol-related disorder in a patient having serum LDL cholesterol levels, comprising at least one anti-PCSK9 antibody at a dose of 14 mg to 480 mg , thereby reducing the cholesterol-related disorder in the patient. A pharmaceutical composition to treat or prevent.

Cholesterol-related disorders include familial hypercholesterolemia, including heterozygous familial hypercholesterolemia and homozygous familial hypercholesterolemia, nonfamilial hypercholesterolemia, elevated lipoprotein (a), heart 56. The pharmaceutical composition according to claim 55 , selected from the group consisting of diseases, metabolic syndrome, diabetes, coronary heart disease, stroke, cardiovascular disease, Alzheimer's disease, peripheral arterial disease, hyperlipidemia, and dyslipidemia Thing .

57. The pharmaceutical composition according to claim 56 , wherein the familial hypercholesterolemia comprises heterozygous familial hypercholesterolemia and homozygous familial hypercholesterolemia.

Patient serum LDL cholesterol levels, a) at least 30% b) at least 40% c) at least 50%, and d) decreases in an amount selected from the group consisting of at least 60% claim 54 or 55 Pharmaceutical composition .

Anti-PCSK9 antibody
(A) a light chain variable region comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 23, and a heavy chain variable region comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 49;
(B) a light chain variable region comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 12, and a heavy chain variable region comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 67;
(C) a light chain variable region comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 461, and a heavy chain variable region comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 459;
(D) a light chain variable region comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 465, and a heavy chain variable region comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 463;
(E) a light chain variable region comprising an amino acid sequence at least 90% identical to SEQ ID NO: 485 and a heavy chain variable region comprising an amino acid sequence at least 90% identical to SEQ ID NO: 483; or (f) A light chain variable region comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 582 and a heavy chain variable region comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 583 , or
(G) the light chain complementarity determining region (CDR) 1 (CDRL1) of the CDRL1 sequence in SEQ ID NO: 23, the CDRL2 sequence of CDRL2 in SEQ ID NO: 23 and the CDRL3 of the CDRL3 sequence in SEQ ID NO: 23, and the heavy chain complementation determination in SEQ ID NO: 49 Region (CDR) 1 (CDRH1), CDRH2 of CDRH2 sequence in SEQ ID NO: 49 and CDRH3 of CDRH3 sequence in SEQ ID NO: 49, or
(H) Light chain complementarity determining region (CDR) 1 (CDRL1) of CDRL1 sequence in SEQ ID NO: 465, CDRL2 sequence of CDRL2 in SEQ ID NO: 465 and CDRL3 of CDRL3 sequence in SEQ ID NO: 465, and heavy chain complementation determination in SEQ ID NO: 463 Region (CDR) 1 (CDRH1), CDRH2 of CDRH2 sequence in SEQ ID NO: 463 and CDRH3 of CDRH3 sequence in SEQ ID NO: 463, or
(I) Light chain complementarity determining region (CDR) 1 (CDRL1) of the CDRL1 sequence in SEQ ID NO: 12, CDRL2 of the CDRL2 sequence in SEQ ID NO: 12 and CDRL3 of the CDRL3 sequence in SEQ ID NO: 12, and heavy chain complementation determination in SEQ ID NO: 67 Region (CDR) 1 (CDRH1), CDRH2 of CDRH2 sequence in SEQ ID NO: 67 and CDRH3 of CDRH3 sequence in SEQ ID NO: 67, or
(J) Light chain complementarity determining region (CDR) 1 (CDRL1) of the CDRL1 sequence in SEQ ID NO: 461, CDRL2 of the CDRL2 sequence in SEQ ID NO: 461 and CDRL3 of the CDRL3 sequence in SEQ ID NO: 461, and heavy chain complementation determination in SEQ ID NO: 459 Region (CDR) 1 (CDRH1), CDRH2 of CDRH2 sequence in SEQ ID NO: 459 and CDRH3 of CDRH3 sequence in SEQ ID NO: 459, or
(K) Light chain complementarity determining region (CDR) 1 (CDRL1) of CDRL1 sequence in SEQ ID NO: 485, CDRL2 sequence of CDRL2 in SEQ ID NO: 485 and CDRL3 of CDRL3 sequence in SEQ ID NO: 485, and heavy chain complementation determination in SEQ ID NO: 483 Region (CDR) 1 (CDRH1), CDRH2 of CDRH2 sequence in SEQ ID NO: 483 and CDRH3 of CDRH3 sequence in SEQ ID NO: 483, or
(L) Light chain complementarity determining region (CDR) 1 (CDRL1) of CDRL1 sequence in SEQ ID NO: 582, CDRL2 sequence of CDRL2 in SEQ ID NO: 582 and CDRL3 of CDRL3 sequence in SEQ ID NO: 582, and heavy chain complementation determination in SEQ ID NO: 583 Region (CDR) 1 (CDRH1), CDRH2 of CDRH2 sequence in SEQ ID NO: 583 and CDRH3 of CDRH3 sequence in SEQ ID NO: 583
59. A pharmaceutical composition according to claim 58 comprising:

Anti-PCSK9 antibody
(A) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 23, and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 49,
(B) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 12, and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 67;
(C) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 461, and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 459,
(D) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 465, and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 463,
(E) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 485, and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 483, or (f) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 582, and SEQ ID NO: 60. The pharmaceutical composition of claim 59 , comprising a heavy chain variable region comprising 583 amino acid sequences.

At least one anti-PCSK9 antibody comprises a light chain complementarity determining region (CDR) 1 (CDRL1) of the CDRL1 sequence in SEQ ID NO: 23, a CDRL2 sequence of CDRL2 in SEQ ID NO: 23 and a CDRL3 sequence of CDRL3 in SEQ ID NO: 23, and SEQ ID NO: 49. 60. The pharmaceutical composition of claim 59, comprising a heavy chain complementarity determining region (CDR) 1 (CDRH1) in SEQ ID NO: 49, CDRH2 in CDRH2 sequence in SEQ ID NO: 49 and CDRH3 in CDRH3 sequence in SEQ ID NO: 49.

A heavy chain comprising CDR1 comprising SEQ ID NO: 308, a CDR2 comprising SEQ ID NO: 175, a CDR3 comprising SEQ ID NO: 180, a light chain comprising CDR1 comprising SEQ ID NO: 158, a CDR2 comprising SEQ ID NO: 162, and a SEQ ID NO: 395 62. The pharmaceutical composition of claim 61 comprising CDR3 comprising

The heavy chain comprises CDR1 comprising SEQ ID NO: 368, CDR2 comprising SEQ ID NO: 175, CDR3 comprising SEQ ID NO: 180, CDR1 comprising light chain comprising SEQ ID NO: 158, CDR2 comprising SEQ ID NO: 162, SEQ ID NO: 395 62. The pharmaceutical composition of claim 61 comprising CDR3 comprising

Anti-PCSK9 antibody is a) 70 mg to 480 mg, b) 105 mg to 480 mg, c) 120 mg to 480 mg, d) 140 mg to 480 mg, e) 150 mg to 480 mg, f) 210 mg to 480 mg, g) 280 mg to 480 mg, h) 300 mg ˜480 mg, i) 350 mg to 480 mg, j) 420 mg to 480 mg, k) 70 mg, l) 105 mg, m) 120 mg, n) 140 mg, o) 150 mg, p) 210 mg, q) 280 mg, r) 300 mg, s) 350 mg 60. The pharmaceutical composition according to claim 59 , wherein t is applied to the patient at a dose selected from the group consisting of 420 mg .

Anti-PCSK9 antibody (1) once a week, (2) once every two weeks, (3) once a month, (4) once every other month, (5) once every three months, (6) 65. The pharmaceutical composition of claim 64 , wherein the composition is applied to a patient for administration on a schedule selected from the group consisting of once every 6 months and (7) once every 12 months.

The pharmaceutical composition of claim 64 which applies step comprises applying at least one anti-PCSK9 antibody parenterally.

65. The pharmaceutical composition of claim 64 , wherein the applying step comprises intravenously applying at least one anti-PCSK9 antibody.

The pharmaceutical composition of claim 64 which applies step comprises at least one anti-PCSK9 antibody subcutaneously applied.

A light chain variable region wherein the at least one anti-PCSK9 antibody comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 23 and a heavy chain variable region comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 49 69. A pharmaceutical composition according to claim 68 comprising

At least one anti-PCSK9 antibody comprises a light chain complementarity determining region (CDR) 1 (CDRL1) of the CDRL1 sequence in SEQ ID NO: 23, a CDRL2 sequence of CDRL2 in SEQ ID NO: 23 and a CDRL3 sequence of CDRL3 in SEQ ID NO: 23, and SEQ ID NO: 49. 69. The pharmaceutical composition of claim 68, comprising: heavy chain complementarity determining region (CDR) 1 (CDRH1) in SEQ ID NO: 49, CDRH2 in CDRH2 sequence in SEQ ID NO: 49 and CDRH3 in CDRH3 sequence in SEQ ID NO: 49.

69. The pharmaceutical composition of claim 68 , wherein the at least one anti-PCSK9 antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 23, and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 49.

71. The pharmaceutical composition of claim 70 , wherein the anti-PCSK9 antibody is subcutaneously applied to the patient once a week at a dose of 14 mg to 45 mg and the patient's serum LDL cholesterol level is reduced by 30 to 70 %.

71. The pharmaceutical composition of claim 70 , wherein the anti-PCSK9 antibody is subcutaneously applied to the patient once every two weeks at a dose of 70 mg to 420 mg, and the patient's serum LDL cholesterol level is reduced by 30 to 70 %.

71. The pharmaceutical composition of claim 70 , wherein the anti-PCSK9 antibody is subcutaneously applied to the patient once a month at a dose of 250 mg to 480 mg, and the patient's serum LDL cholesterol level is reduced by 30 to 70 %.

74. The pharmaceutical composition of claim 73 , wherein the anti-PCSK9 antibody is applied to the patient at a dose of 120 mg.

74. The pharmaceutical composition according to claim 73 , wherein the anti-PCSK9 antibody is applied to the patient at a dose of 140 mg.

75. The pharmaceutical composition according to claim 73 or 74 , wherein the anti-PCSK9 antibody is applied to the patient at a dose of 420 mg.

A light chain variable region wherein the at least one anti-PCSK9 antibody comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 465 and a heavy chain variable region comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 463 60. A pharmaceutical composition according to claim 59 comprising

79. The pharmaceutical composition of claim 78 , wherein the at least one anti-PCSK9 antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 465 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 463.

56. The pharmaceutical composition of claim 55 , wherein at least one anti-PCSK9 antibody is subcutaneously applied to the patient once every two weeks at a dose of 150 mg, and the patient's serum LDL cholesterol level is reduced by at least 30-70 %.

56. The pharmaceutical composition of claim 55 , wherein the anti-PCSK9 antibody is administered to the patient subcutaneously at a dose of 150 mg once every 4 weeks, and the patient's serum LDL cholesterol level is reduced by at least 30-70 %.

Anti-PCSK9 antibody exceeded the 0.99 mg to the patient, and is once subcutaneously four weeks at a dose of up to 2 200 mg, according to claim 55 wherein the patient's serum LDL cholesterol levels reduced by at least 3 0-70% Pharmaceutical composition .

At least one anti-PCSK9 antibody, before at least one other cholesterol lowering agents, according to claim 55 which is applied after at least one other cholesterol lowering agents, or to a patient with at least one other cholesterol-lowering agents Pharmaceutical composition .

At least one other cholesterol-lowering agent is statins including atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin; nicotinic acid; fibric acid; bile acid sequestrant; cholesterol absorption inhibitor; lipid PPAR gamma agonists; PPAR alpha / gamma agonists; squalene synthase inhibitors; CETP inhibitors; antihypertensive agents; antidiabetic agents including sulfonylureas, insulin, GLP-1 analogs, DDPIV inhibitors; ApoB modulators; MTP inhibitors and / or obstructive arteriosclerosis therapy; oncostatin M; estrogen; Belbin; and pharmaceutical composition of claim 83 which is selected from the group consisting of a therapeutic agent for immune related disorders

At least one anti-PCSK9 antibody, before at least one other cholesterol lowering agents, according to claim 70 which is applied after at least one other cholesterol lowering agents, or to a patient with at least one other cholesterol-lowering agents Pharmaceutical composition .

At least one other cholesterol-lowering agent is statins including atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin; nicotinic acid; fibric acid; bile acid sequestrant; cholesterol absorption inhibitor; lipid Modifiers; PPAR gamma agonists; PPAR alpha / gamma agonists; squalene synthase inhibitors; CETP inhibitors; antihypertensive agents; antidiabetic agents including sulfonylureas, insulin, GLP-1 analogs, DDPIV inhibitors; ApoB modulators: MTP inhibitors and / or obstructive arteriosclerosis therapy; oncostatin M; estrogen; Belbin; and pharmaceutical composition of claim 85 which is selected from the group consisting of a therapeutic agent for immune related disorders